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Caspase-1 and Gasdermin D Afford the Optimal Targets with Distinct Switching Strategies in NLRP1b Inflammasome-Induced Cell Death

Inflammasomes are essential complexes of innate immune system, which form the first line of host defense against pathogens. Mounting evidence accumulates that inflammasome signaling is highly correlated with coronavirus disease 2019 (COVID-19). However, there remains a significant gap in our underst...

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Autores principales: Li, Xiang, Zhang, Peipei, Yin, Zhiyong, Xu, Fei, Yang, Zhang-Hua, Jin, Jun, Qu, Jing, Liu, Zhilong, Qi, Hong, Yao, Chenggui, Shuai, Jianwei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: AAAS 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9343085/
https://www.ncbi.nlm.nih.gov/pubmed/35958114
http://dx.doi.org/10.34133/2022/9838341
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author Li, Xiang
Zhang, Peipei
Yin, Zhiyong
Xu, Fei
Yang, Zhang-Hua
Jin, Jun
Qu, Jing
Liu, Zhilong
Qi, Hong
Yao, Chenggui
Shuai, Jianwei
author_facet Li, Xiang
Zhang, Peipei
Yin, Zhiyong
Xu, Fei
Yang, Zhang-Hua
Jin, Jun
Qu, Jing
Liu, Zhilong
Qi, Hong
Yao, Chenggui
Shuai, Jianwei
author_sort Li, Xiang
collection PubMed
description Inflammasomes are essential complexes of innate immune system, which form the first line of host defense against pathogens. Mounting evidence accumulates that inflammasome signaling is highly correlated with coronavirus disease 2019 (COVID-19). However, there remains a significant gap in our understanding of the regulatory mechanism of inflammasome signaling. Combining mathematical modeling with experimental analysis of NLRP1b inflammasome signaling, we found that only the expression levels of caspase-1 and GSDMD have the potential to individually switch cell death modes. Reduction of caspase-1 or GSDMD switches cell death from pyroptosis to apoptosis. Caspase-1 and GSDMD present different thresholds and exert distinct pathway choices in switching death modes. Pyroptosis switches to apoptosis with an extremely low threshold level of caspase-1, but with a high threshold of GSDMD. Caspase-1-impaired cells employ ASC-caspase-8-dependent pathway for apoptosis, while GSDMD-impaired cells primarily utilize caspase-1-dependent pathway. Additionally, caspase-1 and GSDMD can severally ignite the cooccurrence of pyroptosis and apoptosis. Landscape topography unravels that the cooccurrence is dramatically different in caspase-1- and GSDMD-impaired cells. Besides pyroptosis state and apoptosis state, a potential new “coexisting” state in single cells is proposed when GSDMD acts as the driving force of the landscape. The “seesaw model” is therefore proposed, which can well describe the death states that are controlled by caspase-1 or GSDMD in single cells. Our study sheds new light on NLRP1b inflammasome signaling and uncovers the switching mechanisms among various death modes, providing potential clues to guide the development of more rational control strategies for diseases.
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spelling pubmed-93430852022-08-10 Caspase-1 and Gasdermin D Afford the Optimal Targets with Distinct Switching Strategies in NLRP1b Inflammasome-Induced Cell Death Li, Xiang Zhang, Peipei Yin, Zhiyong Xu, Fei Yang, Zhang-Hua Jin, Jun Qu, Jing Liu, Zhilong Qi, Hong Yao, Chenggui Shuai, Jianwei Research (Wash D C) Research Article Inflammasomes are essential complexes of innate immune system, which form the first line of host defense against pathogens. Mounting evidence accumulates that inflammasome signaling is highly correlated with coronavirus disease 2019 (COVID-19). However, there remains a significant gap in our understanding of the regulatory mechanism of inflammasome signaling. Combining mathematical modeling with experimental analysis of NLRP1b inflammasome signaling, we found that only the expression levels of caspase-1 and GSDMD have the potential to individually switch cell death modes. Reduction of caspase-1 or GSDMD switches cell death from pyroptosis to apoptosis. Caspase-1 and GSDMD present different thresholds and exert distinct pathway choices in switching death modes. Pyroptosis switches to apoptosis with an extremely low threshold level of caspase-1, but with a high threshold of GSDMD. Caspase-1-impaired cells employ ASC-caspase-8-dependent pathway for apoptosis, while GSDMD-impaired cells primarily utilize caspase-1-dependent pathway. Additionally, caspase-1 and GSDMD can severally ignite the cooccurrence of pyroptosis and apoptosis. Landscape topography unravels that the cooccurrence is dramatically different in caspase-1- and GSDMD-impaired cells. Besides pyroptosis state and apoptosis state, a potential new “coexisting” state in single cells is proposed when GSDMD acts as the driving force of the landscape. The “seesaw model” is therefore proposed, which can well describe the death states that are controlled by caspase-1 or GSDMD in single cells. Our study sheds new light on NLRP1b inflammasome signaling and uncovers the switching mechanisms among various death modes, providing potential clues to guide the development of more rational control strategies for diseases. AAAS 2022-07-19 /pmc/articles/PMC9343085/ /pubmed/35958114 http://dx.doi.org/10.34133/2022/9838341 Text en Copyright © 2022 Xiang Li et al. https://creativecommons.org/licenses/by/4.0/Exclusive Licensee Science and Technology Review Publishing House. Distributed under a Creative Commons Attribution License (CC BY 4.0).
spellingShingle Research Article
Li, Xiang
Zhang, Peipei
Yin, Zhiyong
Xu, Fei
Yang, Zhang-Hua
Jin, Jun
Qu, Jing
Liu, Zhilong
Qi, Hong
Yao, Chenggui
Shuai, Jianwei
Caspase-1 and Gasdermin D Afford the Optimal Targets with Distinct Switching Strategies in NLRP1b Inflammasome-Induced Cell Death
title Caspase-1 and Gasdermin D Afford the Optimal Targets with Distinct Switching Strategies in NLRP1b Inflammasome-Induced Cell Death
title_full Caspase-1 and Gasdermin D Afford the Optimal Targets with Distinct Switching Strategies in NLRP1b Inflammasome-Induced Cell Death
title_fullStr Caspase-1 and Gasdermin D Afford the Optimal Targets with Distinct Switching Strategies in NLRP1b Inflammasome-Induced Cell Death
title_full_unstemmed Caspase-1 and Gasdermin D Afford the Optimal Targets with Distinct Switching Strategies in NLRP1b Inflammasome-Induced Cell Death
title_short Caspase-1 and Gasdermin D Afford the Optimal Targets with Distinct Switching Strategies in NLRP1b Inflammasome-Induced Cell Death
title_sort caspase-1 and gasdermin d afford the optimal targets with distinct switching strategies in nlrp1b inflammasome-induced cell death
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9343085/
https://www.ncbi.nlm.nih.gov/pubmed/35958114
http://dx.doi.org/10.34133/2022/9838341
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